{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:03:03Z","timestamp":1791928983192,"version":"4.3.4"},"reference-count":91,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,3,1]],"date-time":"2020-03-01T00:00:00Z","timestamp":1583020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Department of Brain Sciences, Imperial College London"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cyclin-dependent kinase-like 5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. It predominantly affects females who typically present with severe early epileptic encephalopathy, global developmental delay, motor dysfunction, autistic features and sleep disturbances. To develop a gene replacement therapy, we initially characterized the human CDKL5 transcript isoforms expressed in the brain, neuroblastoma cell lines, primary astrocytes and embryonic stem cell-derived cortical interneurons. We found that the isoform 1 and to a lesser extent the isoform 2 were expressed in human brain, and both neuronal and glial cell types. These isoforms were subsequently cloned into recombinant adeno-associated viral (AAV) vector genome and high-titre viral vectors were produced. Intrajugular delivery of green fluorescence protein via AAV vector serotype PHP.B in adult wild-type male mice transduced neurons and astrocytes throughout the brain more efficiently than serotype 9. Cdkl5 knockout male mice treated with isoform 1 via intrajugular injection at age 28\u201330 days exhibited significant behavioural improvements compared to green fluorescence protein-treated controls (1012 vg per animal, n\u2009=\u200910 per group) with PHP.B vectors. Brain expression of the isoform 1 transgene was more abundant in hindbrain than forebrain and midbrain. Transgene brain expression was sporadic at the cellular level and most prominent in hippocampal neurons and cerebellar Purkinje cells. Correction of postsynaptic density protein 95 cerebellar misexpression, a major fine cerebellar structural abnormality in Cdkl5 knockout mice, was found in regions of high transgene expression within the cerebellum. AAV vector serotype DJ efficiently transduced CDKL5-mutant human induced pluripotent stem cell-derived neural progenitors, which were subsequently differentiated into mature neurons. When treating CDKL5-mutant neurons, isoform 1 expression led to an increased density of synaptic puncta, while isoform 2 ameliorated the calcium signalling defect compared to green fluorescence protein control, implying distinct functions of these isoforms in neurons. This study provides the first evidence that gene therapy mediated by AAV vectors can be used for treating CDKL5 disorder.<\/jats:p>","DOI":"10.1093\/brain\/awaa028","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T15:09:38Z","timestamp":1579619378000},"page":"811-832","source":"Crossref","is-referenced-by-count":55,"title":["Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder"],"prefix":"10.1093","volume":"143","author":[{"given":"Yunan","family":"Gao","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine E","family":"Irvine","sequence":"first","affiliation":[{"name":"Metabolic Signalling Group, MRC London Institute of Medical Sciences, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Eleftheriadou","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Jim\u00e9nez","family":"Naranjo","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Hearn-Yeates","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leontien","family":"Bosch","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna A","family":"Glegola","sequence":"first","affiliation":[{"name":"Metabolic Signalling Group, MRC London Institute of Medical Sciences, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Murdoch","sequence":"first","affiliation":[{"name":"CBS Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Czerniak","sequence":"first","affiliation":[{"name":"CBS Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Meloni","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Medical Biotechnologies, University of Siena, Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Renieri","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Medical Biotechnologies, University of Siena, Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kinali","sequence":"first","affiliation":[{"name":"The Portland Hospital, 205-209 Great Portland Street, London, W1W 5AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D","family":"Mazarakis","sequence":"first","affiliation":[{"name":"Gene Therapy, Section of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"key":"2020032410380036000_awaa028-B1","doi-asserted-by":"crossref","first-page":"e91613","DOI":"10.1371\/journal.pone.0091613","article-title":"Mapping pathological phenotypes in a mouse model of CDKL5 disorder","volume":"9","author":"Amendola","year":"2014","journal-title":"PLoS One"},{"key":"2020032410380036000_awaa028-B2","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/ejhg.2011.131","article-title":"iPS cells to model CDKL5-related disorders","volume":"19","author":"Amenduni","year":"2011","journal-title":"Eur J Hum Genet"},{"key":"2020032410380036000_awaa028-B6","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1159\/000331333","article-title":"CDKL5-related disorders: from clinical description to molecular genetics","volume":"2","author":"Bahi-Buisson","year":"2012","journal-title":"Mol Syndromol"},{"key":"2020032410380036000_awaa028-B7","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/j.1528-1167.2007.01520.x","article-title":"The three stages of epilepsy in patients with CDKL5 mutations","volume":"49","author":"Bahi-Buisson","year":"2008","journal-title":"Epilepsia"},{"key":"2020032410380036000_awaa028-B8","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.omtm.2018.02.005","article-title":"Development of intrathecal AAV9 gene therapy for giant axonal neuropathy","volume":"9","author":"Bailey","year":"2018","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2020032410380036000_awaa028-B9","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201899763","article-title":"Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics","volume":"37","author":"Baltussen","year":"2018","journal-title":"EMBO J"},{"key":"2020032410380036000_awaa028-B10","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13229-018-0222-8","article-title":"Autism spectrum disorder: prospects for treatment using gene therapy","volume":"9","author":"Benger","year":"2018","journal-title":"Mol Autism"},{"key":"2020032410380036000_awaa028-B11","doi-asserted-by":"crossref","first-page":"32048","DOI":"10.1074\/jbc.M606325200","article-title":"Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation","volume":"281","author":"Bertani","year":"2006","journal-title":"J Biol Chem"},{"key":"2020032410380036000_awaa028-B12","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1038\/mt.2011.157","article-title":"Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders","volume":"19","author":"Bevan","year":"2011","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B13","first-page":"3751","article-title":"Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones","volume":"38","author":"Biedler","year":"1978","journal-title":"Cancer Res"},{"key":"2020032410380036000_awaa028-B14","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.brainres.2004.07.088","article-title":"Potassium channel subunit Kv3.2 and the water channel aquaporin-4 are selectively localized to cerebellar pinceau","volume":"1026","author":"Bobik","year":"2004","journal-title":"Brain Res"},{"key":"2020032410380036000_awaa028-B15","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.nbd.2010.02.014","article-title":"CDKL5 is a brain MeCP2 target gene regulated by DNA methylation","volume":"38","author":"Carouge","year":"2010","journal-title":"Neurobiol Dis"},{"key":"2020032410380036000_awaa028-B16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.devbrainres.2004.03.019","article-title":"Localization of synapsin-I and PSD-95 in developing postnatal rat cerebellar cortex","volume":"151","author":"Castej\u00f3n","year":"2004","journal-title":"Brain Res Dev Brain Res"},{"key":"2020032410380036000_awaa028-B17","doi-asserted-by":"crossref","first-page":"12777","DOI":"10.1523\/JNEUROSCI.1102-10.2010","article-title":"CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling","volume":"30","author":"Chen","year":"2010","journal-title":"J Neurosci"},{"key":"2020032410380036000_awaa028-B18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.neubiorev.2016.01.001","article-title":"The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders","volume":"63","author":"Costales","year":"2016","journal-title":"Neurosci Biobehav Rev"},{"key":"2020032410380036000_awaa028-B19","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.46752","article-title":"Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior","volume":"8","author":"Creson","year":"2019","journal-title":"Elife"},{"key":"2020032410380036000_awaa028-B21","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.bbr.2004.05.027","article-title":"Hippocampal lesions, species-typical behaviours and anxiety in mice","volume":"156","author":"Deacon","year":"2005","journal-title":"Behav Brain Res"},{"key":"2020032410380036000_awaa028-B22","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.biopsych.2015.08.028","article-title":"Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1","volume":"80","author":"Della Sala","year":"2016","journal-title":"Biol Psychiatry"},{"key":"2020032410380036000_awaa028-B23","volume-title":"Neurons\u2014dendrites and axons","author":"Deshmukh","year":"2018"},{"key":"2020032410380036000_awaa028-B24","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nbt.3440","article-title":"Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain","volume":"34","author":"Deverman","year":"2016","journal-title":"Nat Biotechnol"},{"key":"2020032410380036000_awaa028-B25","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/mt.2013.289","article-title":"Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington\u2019s disease mice","volume":"22","author":"Dufour","year":"2014","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B26","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1126\/science.290.5495.1364","article-title":"PSD-95 involvement in maturation of excitatory synapses","volume":"290","author":"El-Husseini","year":"2000","journal-title":"Science"},{"key":"2020032410380036000_awaa028-B27","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1866-1955-7-2","article-title":"There is variability in the attainment of developmental milestones in the CDKL5 disorder","volume":"7","author":"Fehr","year":"2015","journal-title":"J Neurodev Disord"},{"key":"2020032410380036000_awaa028-B28","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/ejhg.2012.156","article-title":"The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy","volume":"21","author":"Fehr","year":"2013","journal-title":"Eur J Hum Genet"},{"key":"2020032410380036000_awaa028-B29","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1212\/WNL.0000000000003352","article-title":"Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder","volume":"87","author":"Fehr","year":"2016","journal-title":"Neurology"},{"key":"2020032410380036000_awaa028-B30","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/jhg.2010.143","article-title":"An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain","volume":"56","author":"Fichou","year":"2011","journal-title":"J Hum Genet"},{"key":"2020032410380036000_awaa028-B31","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nbt.1515","article-title":"Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes","volume":"27","author":"Foust","year":"2009","journal-title":"Nat Biotechnol"},{"key":"2020032410380036000_awaa028-B32","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/mt.2011.34","article-title":"Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery","volume":"19","author":"Fu","year":"2011","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B33","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.ymthe.2003.08.021","article-title":"Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain","volume":"8","author":"Fu","year":"2003","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B34","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/ejn.13923","article-title":"Treatment with the GSK3-beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice","volume":"47","author":"Fuchs","year":"2018","journal-title":"Eur J Neurosci"},{"key":"2020032410380036000_awaa028-B35","doi-asserted-by":"crossref","first-page":"9726950","DOI":"10.1155\/2018\/9726950","article-title":"Heterozygous CDKL5 knockout female mice are a valuable animal model for CDKL5 disorder","volume":"2018","author":"Fuchs","year":"2018","journal-title":"Neural Plast"},{"key":"2020032410380036000_awaa028-B36","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.nbd.2015.06.018","article-title":"Inhibition of GSK3\u03b2 rescues hippocampal development and learning in a mouse model of CDKL5 disorder","volume":"82","author":"Fuchs","year":"2015","journal-title":"Neurobiol Dis"},{"key":"2020032410380036000_awaa028-B37","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.nbd.2014.06.006","article-title":"Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT\/GSK-3\u03b2 signaling","volume":"70","author":"Fuchs","year":"2014","journal-title":"Neurobiol Dis"},{"key":"2020032410380036000_awaa028-B38","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.omtm.2017.04.007","article-title":"Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome","volume":"5","author":"Gadalla","year":"2017","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2020032410380036000_awaa028-B39","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1523\/JNEUROSCI.1854-13.2013","article-title":"Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome","volume":"33","author":"Garg","year":"2013","journal-title":"J Neurosci"},{"key":"2020032410380036000_awaa028-B40","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1038\/npp.2014.167","article-title":"Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice","volume":"39","author":"Gholizadeh","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"2020032410380036000_awaa028-B41","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/stem.587","article-title":"A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives","volume":"29","author":"Goulburn","year":"2011","journal-title":"Stem Cells"},{"key":"2020032410380036000_awaa028-B42","author":"Gray","year":"2011"},{"key":"2020032410380036000_awaa028-B43","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1089\/hum.2010.245","article-title":"Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors","volume":"22","author":"Gray","year":"2011","journal-title":"Hum Gene Ther"},{"key":"2020032410380036000_awaa028-B44","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/gt.2012.101","article-title":"Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates","volume":"20","author":"Gray","year":"2013","journal-title":"Gene Ther"},{"key":"2020032410380036000_awaa028-B45","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1128\/JVI.00254-08","article-title":"In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses","volume":"82","author":"Grimm","year":"2008","journal-title":"J Virol"},{"key":"2020032410380036000_awaa028-B48","doi-asserted-by":"crossref","first-page":"e0157758","DOI":"10.1371\/journal.pone.0157758","article-title":"Characterisation of CDKL5 transcript isoforms in human and mouse","volume":"11","author":"Hector","year":"2016","journal-title":"PLoS One"},{"key":"2020032410380036000_awaa028-B49","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.gene.2016.12.001","article-title":"Characterisation of Cdkl5 transcript isoforms in rat","volume":"603","author":"Hector","year":"2017","journal-title":"Gene"},{"key":"2020032410380036000_awaa028-B50","doi-asserted-by":"crossref","first-page":"e200","DOI":"10.1212\/NXG.0000000000000200","article-title":"CDKL5 variants: improving our understanding of a rare neurologic disorder","volume":"3","author":"Hector","year":"2017","journal-title":"Neurol Genet"},{"key":"2020032410380036000_awaa028-B51","doi-asserted-by":"crossref","first-page":"9438","DOI":"10.1523\/JNEUROSCI.1651-12.2012","article-title":"Lack of molecular-anatomical evidence for GABAergic influence on axon initial segment of cerebellar Purkinje cells by the pinceau formation","volume":"32","author":"Iwakura","year":"2012","journal-title":"J Neurosci"},{"key":"2020032410380036000_awaa028-B52","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1093\/hmg\/ddx279","article-title":"Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors","volume":"26","author":"Jhang","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B53","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1086\/375538","article-title":"Disruption of the serine\/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation","volume":"72","author":"Kalscheuer","year":"2003","journal-title":"Am J Hum Genet"},{"key":"2020032410380036000_awaa028-B54","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.bbrc.2008.10.113","article-title":"Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1","volume":"377","author":"Kameshita","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"2020032410380036000_awaa028-B55","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1073\/pnas.1007753108","article-title":"Investigating synapse formation and function using human pluripotent stem cell-derived neurons","volume":"108","author":"Kim","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020032410380036000_awaa028-B56","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1074\/jbc.M114.589762","article-title":"Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5","volume":"290","author":"La Montanara","year":"2015","journal-title":"J Biol Chem"},{"key":"2020032410380036000_awaa028-B57","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.brainresrev.2011.02.005","article-title":"Brain regions and genes affecting limb-clasping responses","volume":"67","author":"Lalonde","year":"2011","journal-title":"Brain Res Rev"},{"key":"2020032410380036000_awaa028-B58","doi-asserted-by":"crossref","first-page":"9397","DOI":"10.1073\/pnas.0802876105","article-title":"Transcription factor MEF2C influences neural stem\/progenitor cell differentiation and maturation in vivo","volume":"105","author":"Li","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020032410380036000_awaa028-B59","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/j.ymthe.2019.07.017","article-title":"AAV-PHP.B administration results in a differential pattern of CNS biodistribution in non-human primates compared with mice","volume":"27","author":"Liguore","year":"2019","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B60","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1093\/hmg\/ddi391","article-title":"CDKL5\/Stk9 kinase inactivation is associated with neuronal developmental disorders","volume":"14","author":"Lin","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B61","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ejhg.2014.81","article-title":"GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells","volume":"23","author":"Livide","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"2020032410380036000_awaa028-B62","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1093\/hmg\/ddi198","article-title":"CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome","volume":"14","author":"Mari","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B63","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1002\/ajmg.a.33037","article-title":"Somatic mosaicism for a CDKL5 mutation as an epileptic encephalopathy in males","volume":"152A","author":"Masliah-Plachon","year":"2010","journal-title":"Am J Med Genet A"},{"key":"2020032410380036000_awaa028-B64","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.neulet.2017.11.049","article-title":"Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain","volume":"665","author":"Matsuzaki","year":"2018","journal-title":"Neurosci Lett"},{"key":"2020032410380036000_awaa028-B65","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1038\/gt.2009.85","article-title":"Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice","volume":"16","author":"McCarty","year":"2009","journal-title":"Gene Ther"},{"key":"2020032410380036000_awaa028-B66","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1111\/epi.12803","article-title":"Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys","volume":"55","author":"Mei","year":"2014","journal-title":"Epilepsia"},{"key":"2020032410380036000_awaa028-B67","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N Engl J Med"},{"key":"2020032410380036000_awaa028-B68","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.pediatrneurol.2012.12.030","article-title":"CDKL5 and ARX mutations in males with early-onset epilepsy","volume":"48","author":"Mirzaa","year":"2013","journal-title":"Pediatr Neurol"},{"key":"2020032410380036000_awaa028-B69","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1006\/geno.1998.5391","article-title":"Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region","volume":"51","author":"Montini","year":"1998","journal-title":"Genomics"},{"key":"2020032410380036000_awaa028-B70","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201899559","article-title":"Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase","volume":"37","author":"Mu\u00f1oz","year":"2018","journal-title":"EMBO J"},{"key":"2020032410380036000_awaa028-B71","doi-asserted-by":"crossref","first-page":"e0148634","DOI":"10.1371\/journal.pone.0148634","article-title":"CDKL5 and shootin1 interact and concur in regulating neuronal polarization","volume":"11","author":"Nawaz","year":"2016","journal-title":"PLoS One"},{"key":"2020032410380036000_awaa028-B72","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.stem.2013.04.005","article-title":"Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development","volume":"12","author":"Nicholas","year":"2013","journal-title":"Cell Stem Cell"},{"key":"2020032410380036000_awaa028-B73","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.nbd.2017.07.002","article-title":"CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility","volume":"106","author":"Okuda","year":"2017","journal-title":"Neurobiol Dis"},{"key":"2020032410380036000_awaa028-B74","doi-asserted-by":"crossref","first-page":"e0196587","DOI":"10.1371\/journal.pone.0196587","article-title":"Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory","volume":"13","author":"Okuda","year":"2018","journal-title":"PLoS One"},{"key":"2020032410380036000_awaa028-B76","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3389\/fncel.2016.00261","article-title":"Lack of Cdkl5 disrupts the organization of excitatory and inhibitory synapses and parvalbumin interneurons in the primary visual cortex","volume":"10","author":"Pizzo","year":"2016","journal-title":"Front Cell Neurosci"},{"key":"2020032410380036000_awaa028-B77","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1152\/jn.2000.84.2.710","article-title":"alpha-SNS produces the slow TTX-resistant sodium current in large cutaneous afferent DRG neurons","volume":"84","author":"Renganathan","year":"2000","journal-title":"J Neurophysiol"},{"key":"2020032410380036000_awaa028-B78","doi-asserted-by":"crossref","first-page":"4590","DOI":"10.1093\/hmg\/ddp426","article-title":"CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery","volume":"18","author":"Ricciardi","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B79","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/ncb2566","article-title":"CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons","volume":"14","author":"Ricciardi","year":"2012","journal-title":"Nat Cell Biol"},{"key":"2020032410380036000_awaa028-B80","doi-asserted-by":"crossref","first-page":"30101","DOI":"10.1074\/jbc.M804613200","article-title":"CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail","volume":"283","author":"Rusconi","year":"2008","journal-title":"J Biol Chem"},{"key":"2020032410380036000_awaa028-B81","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.biopsych.2017.09.021","article-title":"Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells","volume":"83","author":"Russo","year":"2018","journal-title":"Biol Psychiatry"},{"key":"2020032410380036000_awaa028-B82","first-page":"S305","article-title":"Safety and increased transduction efficiency in the adult nonhuman primate central nervous system with intravenous delivery of two novel adeno-associated virus capsids [Abstract O661]. American Society of Gene and Cell Therapy Annual Meeting. Chicago, USA","volume":"26 (Suppl 1","author":"Sah","year":"2018","journal-title":"Mol Ther"},{"key":"2020032410380036000_awaa028-B83","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.neuroimage.2014.12.003","article-title":"Rotarod training in mice is associated with changes in brain structure observable with multimodal MRI","volume":"107","author":"Scholz","year":"2015","journal-title":"Neuroimage"},{"key":"2020032410380036000_awaa028-B84","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.abb.2013.04.012","article-title":"Identification of amphiphysin 1 as an endogenous substrate for CDKL5, a protein kinase associated with X-linked neurodevelopmental disorder","volume":"535","author":"Sekiguchi","year":"2013","journal-title":"Arch Biochem Biophys"},{"key":"2020032410380036000_awaa028-B85","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/gbb.12292","article-title":"CDKL5 knockout leads to altered inhibitory transmission in the cerebellum of adult mice","volume":"15","author":"Sivilia","year":"2016","journal-title":"Genes Brain Behav"},{"key":"2020032410380036000_awaa028-B86","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/cne.21774","article-title":"Immunohistochemical description of the endogenous cannabinoid system in the rat cerebellum and functionally related nuclei","volume":"509","author":"Su\u00e1rez","year":"2008","journal-title":"J Comp Neurol"},{"key":"2020032410380036000_awaa028-B87","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/ejhg.2014.217","article-title":"Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications","volume":"23","author":"Szafranski","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"2020032410380036000_awaa028-B88","doi-asserted-by":"crossref","first-page":"7420","DOI":"10.1523\/JNEUROSCI.0539-17.2017","article-title":"Loss of CDKL5 in glutamatergic neurons disrupts hippocampal microcircuitry and leads to memory impairment in mice","volume":"37","author":"Tang","year":"2017","journal-title":"J Neurosci"},{"key":"2020032410380036000_awaa028-B89","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/ajmg.a.33340","article-title":"Clinical and molecular characterization of overlapping interstitial Xp21-p22 duplications in two unrelated individuals","volume":"152A","author":"Thorson","year":"2010","journal-title":"Am J Med Genet A"},{"key":"2020032410380036000_awaa028-B90","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1093\/hmg\/ddy064","article-title":"CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder","volume":"27","author":"Trazzi","year":"2018","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B91","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1093\/hmg\/ddw231","article-title":"HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder","volume":"25","author":"Trazzi","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2020032410380036000_awaa028-B92","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/ajmg.a.32070","article-title":"Characterization of interstitial Xp duplications in two families by tiling path array CGH","volume":"146A","author":"Tzschach","year":"2008","journal-title":"Am J Med Genet A"},{"key":"2020032410380036000_awaa028-B93","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/ajmg.a.31572","article-title":"Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes","volume":"143","author":"Van Esch","year":"2007","journal-title":"Am J Med Genet A"},{"key":"2020032410380036000_awaa028-B94","doi-asserted-by":"crossref","first-page":"21516","DOI":"10.1073\/pnas.1216988110","article-title":"Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice","volume":"109","author":"Wang","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020032410380036000_awaa028-B95","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/wdev.65","article-title":"Development of the cerebellum: from gene expression patterns to circuit maps","volume":"2","author":"White","year":"2013","journal-title":"Wires Dev Biol"},{"key":"2020032410380036000_awaa028-B96","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00439-011-1058-x","article-title":"A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain","volume":"131","author":"Williamson","year":"2012","journal-title":"Hum Genet"},{"key":"2020032410380036000_awaa028-B97","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3389\/fnins.2019.00349","article-title":"Neurological diseases with autism spectrum disorder: role of autism spectrum disorder risk genes","volume":"13","author":"Xiong","year":"2019","journal-title":"Front Neurosci"},{"key":"2020032410380036000_awaa028-B99","doi-asserted-by":"crossref","first-page":"9118","DOI":"10.1073\/pnas.1300003110","article-title":"Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development","volume":"110","author":"Zhu","year":"2013","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/143\/3\/811\/32963701\/awaa028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/143\/3\/811\/32963701\/awaa028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T02:13:32Z","timestamp":1665540812000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/143\/3\/811\/5775569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,1]]},"references-count":91,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3,3]]},"published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awaa028","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2020,3,1]]}}}